The mature hemicastrated male rat is a unique model in which to study testicular regulation. Although the testis in a hemicastrated rat does not undergo compensatory hypertrophy (as do ovaries, adrenals and thyroids under similar circumstances), testosterone (T) in the spermatic vein effluent doubles within a few hours (designated the testicular hemicastration response). Similarly, systemic plasma T is restored to a normal concentration. This occurs without any evident change in plasma LH and prolactin, while plasma FSH rises much too late (2-3 d) to account for a surge in T secretion in the hemicastrated testis. There is no change in LH receptors (unoccupied or occupied) in the testis. If plasma LH concentrations are involved, they are only permissive; the response does not occur in a hypophysectomized rat. Meanwhile, there is no change in testicular blood flow. Based on published and unpublished data, we propose that the testicular hemicastration response is initiated by denervation of the contralateral testis (both superior and inferior spermatic plexi), which then mediates a change in the time that membrane-bound LH remains on the cell surface before it internalizes. We propose to demonstrate initiation in vivo by varied studies of denervation (we have already partially suppressed the hemicastration response by cutting the inferior spermatic nerve). We propose to explore the mechanism in vitro by studying the perfused testis, the decapsulated testis, purified interstitial cells, and perifused interstitial cells (we have already maintained the testicular hemicastration response in decapsulated hemicastrated testes for 3 h). The fact that the response can be maintained in vitro suggests that a fundamental change has taken place in the Leydig cell. It would be hard to believe that the mechanism by which Leydig cells change in hemicastration is not also a factor in the normal regulation of the testis. These studies are among the few current studies of hemicastration in the mammal, which is a common surgical procedure in humans for testicular cancer and prepubertal cryptorchidism.